IL-1alpha has antiproliferative activity against human melanoma cell lines, causes murine melanoma tumors to shrink in vivo, can induce interferons and interleukin-2 which have activity in melanoma, and can enhance the activity of cytotoxic T cells and other effector cells. Animal studies suggested that indomethacin increased the antitumor effects of IL-1. For these reasons, we designed this phase II study in melanoma patients to determine the anti-tumor activity of IL-1alpha plus indomethacin using the maximum tolerated dose of IL-1alpha from our earlier phase I trial. A total of 36 patients have entered the study, and 32 are evaluable for response. No patient with predominately visceral metastases responded to treatment. One patient with non-visceral metastases had a partial response and one patient had a minor response. These results indicate that IL-1alpha has a low level of activity in melanoma. In an effort to enhance this activity, we are planning a follow-up clinical trial that combines etoposide (VP-16) with this regimen based on preclinical studies that have demonstrated synergy of the combination.